Dihydropyrimidine dehydrogenase deficiency

Dihydropyrimidine dehydrogenase deficiency is an autosomal recessive
metabolic disorder in which there is absent or significantly decreased activity of dihydropyrimidine dehydrogenase, an enzyme involved in the metabolism of uracil and thymine.
Individuals with this condition may develop life-threatening toxicity following exposure to 5-fluorouracil, a chemotherapy drug that is used in the treatment of cancer. Beside 5-FU, widely prescribed oral fluoropyrimidine capecitabine could put DPD-deficient patients at risk of experiencing severe or lethal toxicities as well.

Presentation

Genetics

DPD deficiency is inherited in an autosomal recessive manner. This means the defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.

Diagnosis

Detection

A small number of genetic variants have been repeatedly associated with DPD deficiency, such as IVS14+1G>A mutation in intron 14 coupled with exon 14 deletion, 496A>G in exon 6; 2846A>T in exon 22 and T1679G in exon 13. Testing patients for these allelic variants usually show high specificity but very low sensitivity. Alternatively, phenotyping DPD using ex-vivo enzymatic assay or surrogate testing has been presented as a possible upfront strategy to detect DPD deficiency. 5-FU test dose has been proposed as another possible alternative strategy to secure the use of fluoropyrimidine drugs.. The Clinical Pharmacogenetics Implementation Consortium has issued guidelines supporting 50% dose reduction in heterozygous carriers of the decreased function variants rs3918290, rs55886062, rs56038477, rs67376798, c.2846A>T or c.1129–5923C>G
Although DPYD pre-treatment screening has been proven to improve drug safety for DPYD*2A carriers by the Food and Drug Administration, the current European Society for Medical Oncology guidelines do not “routinely recommend” upfront genotyping of DPYD*2A before the administration of 5‐FU in metastatic CRC patients. While oncology societies in the United States do not recommend systematic testing. Instead, on April 30, 2020, the European Society for Medical Oncology issued a document recommending genetic testing. France is the first and only country to require pre-dose DPD testing before administering 5-FU or capecitabine in 2018.